Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single nucleotide polymorphisms (SNPs) with the lowest p-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI related loci was performed in the AN GWAMA. We detected significant associations (p-values < 5×10−5, Bonferroni corrected p < 0.05) for 9 SNP alleles at 3 independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; poverall: 2.47 × 10−06/pfemales: 3.45 × 10−07/pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet induced obese (DIO) mice as compared to age-matched lean controls. We observed no evidence for associations for the look-up of BMI related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation

Inkretinbasierte Medikamente zur Diabetes- und Adipositastherapie. Entwicklungsperspektiven. &nbsp;

Background: Along with the global increase in obesity, type 2 diabetes continues to spread worldwide. Thus, safe and effective treatment options are urgently needed because nonpharmacological treatment options, including lifestyle changes in diet and physical activity, fail to achieve sustained weight loss and glycemic control. Objectives: An overview of established therapeutic options in the treatment of obesity is presented with a focus on the discovery and translational relevance of new polyagonist-based therapies. Materials and methods: Recently published trials in the development and application of monomeric peptide-based polyagonists and peptide-based transport of steroid and thyroid hormones to treat obesity and diabetes are summarized and assessed. Results: Currently available pharmacological attempts to treat obesity have limited success with notable adverse effects. More promising are novel unimolecular hormonal polyagonists that have the unique potential to reverse obesity and diabetes in animal models. These activate up to three receptors with similar affinity. Beneficial effects on body weight and blood sugar levels in animals have been observed in preclinical research with a GLP-1/glucagon coagonist (GLP: glucagon-like peptide), a GLP-1/GIP coagonist (GIP: glucose-dependent insulinotropic polypeptide), and a GLP-1/GIP/glucagon triagonist. Similar positive effects could be demonstrated for steroid and thyroid hormones which are transported to specific tissues using a peptide transport molecule. Particularly promising are GLP-1/estrogen and glucagon/T3 (triiodothyronine). Conclusions: This article provides an overview of established therapeutic options in the treatment of obesity and focuses on the discovery and translational relevance of new polyagonist-based therapies

Pharmacological targeting of α3β4 nicotinic receptors improves peripheral insulin sensitivity in mice with diet-induced obesity

Aims/hypothesis Treatment with the alpha 3 beta 4 nicotinic acetylcholine receptor (nAChR) agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), improves glucose tolerance in diet-induced obese (DIO) mice, but the physiological and molecular mechanisms are unknown. Methods DMPP (10 mg/kg body weight, s.c.) was administered either in a single injection (acute) or daily for up to 14 days (chronic) in DIO wild-type (WT) and Chrnb4 knockout (KO) mice and glucose tolerance, tissue-specific tracer-based glucose metabolism, and insulin signalling were assessed. Results In WT mice, but not in Chrnb4 KO mice, single acute treatment with DMPP induced transient hyperglycaemia, which was accompanied by high plasma adrenaline (epinephrine) levels, upregulated hepatic gluconeogenic genes, and decreased hepatic glycogen content. In contrast to these acute effects, chronic DMPP treatment in WT mice elicited improvements in glucose tolerance already evident after three consecutive days of DMPP treatment. After seven days of DMPP treatment, glucose tolerance was markedly improved, also in comparison with mice that were pair-fed to DMPP-treated mice. The glycaemic benefit of chronic DMPP was absent in Chrnb4 KO mice. Chronic DMPP increased insulin-stimulated glucose clearance into brown adipose tissue (+69%), heart (+93%), gastrocnemius muscle (+74%) and quadriceps muscle (+59%), with no effect in white adipose tissues. After chronic DMPP treatment, plasma adrenaline levels did not increase following an injection with DMPP. In glucose-stimulated skeletal muscle, we detected a decreased phosphorylation of the inhibitory Ser640 phosphorylation site on glycogen synthase and a congruent increase in glycogen accumulation following chronic DMPP treatment. Conclusions/interpretation Our data suggest that DMPP acutely induces adrenaline release and hepatic glycogenolysis, while chronic DMPP-mediated activation of beta 4-containing nAChRs improves peripheral insulin sensitivity independently of changes in body weight via mechanisms that could involve increased non-oxidative glucose disposal into skeletal muscle

Plasma proteome profiles treatment efficacy of incretin dual agonism in diet-induced obese female and male mice.

Aims Unimolecular peptides targeting the receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (GLP-1/GIP co-agonist) have been shown to outperform each single peptide in the treatment of obesity and cardiometabolic disease in preclinical and clinical trials. By combining physiological treatment endpoints with plasma proteomic profiling (PPP), we aimed to identify biomarkers to advance non-invasive metabolic monitoring of compound treatment success and exploration of ulterior treatment effects on an individual basis.Materials and methods We performed metabolic phenotyping along with PPP in body weight-matched male and female diet-induced obese (DIO) mice treated for 21 days with phosphate-buffered saline, single GIP and GLP-1 mono-agonists, or a GLP-1/GIP co-agonist.Results GLP-1R/GIPR co-agonism improved obesity, glucose intolerance, non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia with superior efficacy in both male and female mice compared with mono-agonist treatments. PPP revealed broader changes of plasma proteins after GLP-1/GIP co-agonist compared with mono-agonist treatments in both sexes, including established and potential novel biomarkers for systemic inflammation, NAFLD and atherosclerosis. Subtle sex-specific differences have been observed in metabolic phenotyping and PPP.Conclusions We herein show that a recently developed unimolecular GLP-1/GIP co-agonist is more efficient in improving metabolic disease than either mono-agonist in both sexes. PPP led to the identification of a sex-independent protein panel with the potential to monitor non-invasively the treatment efficacies on metabolic function of this clinically advancing GLP-1/GIP co-agonist

Pharmacological targeting of α3β4 nicotinic receptors improves peripheral insulin sensitivity in mice with diet-induced obesity

ims/hypothesisTreatment with theα3β4 nicotinic acetylcholine receptor (nAChR) agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), improves glucose tolerance in diet-induced obese (DIO) mice, but the physiological andmolecular mechanisms are unknown.MethodsDMPP (10 mg/kg body weight, s.c.) was administered either in a single injection (acute) or daily for up to 14 days(chronic) in DIO wild-type (WT) andChrnb4knockout (KO) mice and glucose tolerance, tissue-specific tracer-based glucosemetabolism, and insulin signalling were assessed.ResultsIn WT mice, but not inChrnb4KO mice, single acute treatment with DMPP induced transient hyperglycaemia,which was accompanied by high plasma adrenaline (epinephrine) levels, upregulated hepatic gluconeogenic genes, anddecreased hepatic glycogen content. In contrast to theseacute effects, chronic DMPP treatment in WT mice elicitedimprovements in glucose tolerance already evident after three consecutive days of DMPP treatment. After seven days ofDMPP treatment, glucose tolerance was markedly improved,alsoincomparisonwithmicethatwerepair-fedtoDMPP-treated mice. The glycaemic benefit of chronic DMPP was absent inChrnb4KO mice. Chronic DMPP increased insulin-stimulated glucose clearance into brown adipose tissue(+69%), heart (+93%), gastrocnemius muscle (+74%) andquadriceps muscle (+59%), with no effect in white adipose tissues. After chronic DMPP treatment, plasma adrenalinelevels did not increase following an injection with DMPP. In glucose-stimulated skeletal muscle, we detected a decreasedphosphorylation of the inhibitory Ser640 phosphorylation site on glycogen synthase and a congruent increase in glyco-gen accumulation following chronic DMPP treatment.Conclusions/interpretationOur data suggest that DMPP acutely induces adrenaline release and hepatic glycogenolysis,while chronic DMPP-mediated activation ofβ4-containing nAChRs improves peripheral insulin sensitivity independent-ly of changes in body weight via mechanisms that could involve increased non-oxidative glucose disposal into skeletalmuscle.publishe

Adipocyte glucocorticoid receptor deficiency attenuates aging and HFDinduced obesity, and impairs the feedingfasting transition.

Glucocorticoids (GCs) are important regulators of systemic energy metabolism, while aberrant GC action is linked to metabolic dysfunctions. Yet, the extent to which normal and pathophysiologic energy metabolism depend on the glucocorticoid receptor (GR) in adipocytes remains unclear. Here, we demonstrate that adipocyte GR-deficiency in mice significantly impacts systemic metabolism in different energetic states. Plasma metabolomics and biochemical analyses revealed a marked global effect of GR-deficiency on systemic metabolite abundance and thus, substrate partitioning in fed and fasted states. This correlated with a decreased lipolytic capacity of GR-deficient adipocytes under post-absorptive and fasting conditions, resulting from impaired signal transduction from &beta;-adrenergic receptors to adenylate cyclase. Upon prolonged fasting, the impaired lipolytic response resulted in abnormal substrate utilization and lean mass wasting. Conversely, GR-deficiency attenuated aging-/diet-associated obesity, adipocyte hypertrophy and liver steatosis. Systemic glucose tolerance was improved in obese GR-deficient mice, which was associated with increased insulin signaling in muscle and adipose tissue.We conclude that the GR in adipocytes exerts central, but diverging roles in the regulation of metabolic homeostasis depending on the energetic state: The adipocyte GR is indispensable for the feeding-fasting transition, but also promotes adiposity and associated metabolic disorders in fat-fed and aged mice